Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](SC)=[N:14][C:13](=[O:19])[N:12]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][NH2:26]>>[CH2:1]([N:8]1[C:16]2/[C:15](=[N:25]/[NH2:26])/[NH:14][C:13](=[O:19])[N:12]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCn1c(=O)nc(SC)c2c1ncn2Cc1ccccc1
Reactant: NN
Product: CCCCCn1c(=O)[nH]/c(=N\N)c2c1ncn2Cc1ccccc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
7-Benzyl-6-(methylthio)-3-pentyl-3,7-dihydro-2H-purin-2-one (1.2 g, 3.5 mmol) and hydrazine (10 mL, 100 mmol) were mixed. After being stirred at 100° C. overnight, the solution was concentrated in vacuum. The residue was dissolved in DMSO and purified using preparative LCMS. The product fractions were collected and lyophilized to provide the product as a white powder (0.56 g, 60% yield). LCMS calculated for C17H23N6O (M+H): 327.2. found: 327.1.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](O)([C:13]1[S:17][N:16]=[CH:15][CH:14]=1)[CH2:8][CH2:7][CH2:6]2)#[N:2].S(Cl)(Cl)=O.N1CCOCC1>C1C=CC=CC=1>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]1[S:17][N:16]=[CH:15][CH:14]=1)=[CH:8][CH2:7][CH2:6]2)#[N:2]
Reactant: N#Cc1ccc2c(c1)CCCC2(O)c1ccns1
Solvent: C1COCCN1
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: N#Cc1ccc2c(c1)CCC=C2c1ccns1

Procedure:
Analogously to Example 13, 92 mg of 6-cyano-1-hydroxy-1-(5-isothiazolyl)-1,2,3,4-tetrahydronaphthalene (Example 15) and 0.051 ml of thionyl chloride in 0.32 of benzene, with the subsequent addition of 0.112 ml of morpholine, are converted into the crude title compound, which is purified by column chromatography (SiO2, 0.1 bar, hexane/ethyl acetate 4:1) and crystallisation from hexane; m.p. 77°-81°; 1H-NMR (CECl3): δ(ppm)=2.5 (m,2H), 2.92 (t,2H), 6.54 (t,2H), 7.2 (d,1H), 7.29 (d,1H), 7.5 (dd,1H), 7.55 (d,1H), 8.5 (d,1H).
Reaction SMILES: [I-:1].[Na+].CNC1CCCCC1NC.Br[C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[CH:19][CH:18]=[CH:17]2>O1CCOCC1.[Cu]I>[I:1][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[CH:19][CH:18]=[CH:17]2
Reactant: [I-]
Reactant: Brc1ccc2ncccc2c1
Agent: [Cu]I
Agent: CNC1CCCCC1NC
Agent: [Na+]
Solvent: C1COCCO1
Product: Ic1ccc2ncccc2c1
Temperature: 110 °C
Reaction time: 15 h

Procedure:
Sodium iodide (4.32 g, 28.8 mmol), Copper (I) iodide (137 mg, 0.72 mmol) and N,N′-Dimethyl-cyclohexane-1,2-diamine (0.227 mL, 1.44 mmol) and 6-Bromoquinoline (3 g, 14.4 mmol) in dioxane (15 mL) were charged in a 25 mL microwave tube. The tube was flushed with Nitrogen and sealed with a Teflon septum and Nitrogen was bubbled in the solution for 10 minutes, allowing the gas to escape through a needle. After the removal of the needle, the reaction mixture was stirred at 110° C. for 15 hours. Then, the green suspension was allowed to reach room temperature, poured into ice-water and extracted with dichloromethane. The organic layer was collected, dried (MgSO4), filtered and concentrated in vacuum. The crude mixture was chromatographied over silica gel with CH2Cl2 100% and CH2Cl2/MeOH:95/5 to yield 3.56 g (97%) of 6-Todoquinoline as a light yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:20](=[O:28])[CH2:21]P(OC)(OC)=O)[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[Cl-].[Li+].[F:40][C:41]([F:55])([F:54])[C:42]1[CH:43]=[C:44]([CH:47]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:49]=1)[CH:45]=O>C(#N)C>[F:40][C:41]([F:54])([F:55])[C:42]1[CH:43]=[C:44]([CH:45]=[CH:21][C:20](=[O:28])[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH:47]=[C:48]([C:50]([F:51])([F:52])[F:53])[CH:49]=1
Reactant: COP(=O)(CC(=O)C(Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)OC
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC(Cc1c[nH]c2ccccc12)C(=O)C=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 2 h

Procedure:
A solution of the product of part (b) (69.0 g) in acetonitrile (600 ml) was stirred with diisopropylethylamine (43.3 g), and anhydrous lithium chloride (14.13 g) for 30 minutes before adding 3,5-bistrifluoromethylbenzaldehyde (55 g) in acetonitrile (200 ml). The reaction was stirred for two hours then the solvent was removed and the residue partitioned between ethyl acetate and water. The organic phase was washed with 10% citric acid (500 ml), water (500 ml), saturated sodium bicarbonate (500 ml) and water (500 ml). The solution was dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography on silica using ethyl acetate/petroleum ether (1:4) to yield the title compound as a pale yellow solid, mp=137°-138° C.; found: C, 59.23; H, 4.79; N, 5.35; C26H24F6N2O3 requires C, 59.32; H, 4.60; N 5.32%.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)N)=[CH:5][CH:4]=1.C(O[CH:23](OCC)[CH2:24][CH2:25][CH2:26][NH:27][CH3:28])C>C(O)C.O>[Cl:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[N:9]([CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:23]=[C:24]2[CH2:25][CH2:26][NH:27][CH3:28]
Reactant: CCOC(CCCNC)OCC
Reactant: NN(CCCc1ccccc1)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CNCCc1cn(CCCc2ccccc2)c2ccc(Cl)cc12
Temperature: 90 °C
Yield: 74.3 %

Procedure:
28% aqueous HCl (0.07 mL, 0.54 mmol) was added to a solution of N-(4-Chloro-phenyl)-N-(3-phenyl-propyl)-hydrazine (261 mg, 1 mmol) in ethanol (1 mL) and water (0.5 mL) under a nitrogen atmosphere. The reaction was heated to 60° C. (oil bath temperature) and 4,4-diethoxy-N-methylbutan-1-amine (175 mg, 1 mmol) was added. The reaction was heated to 90° C. and 28% aqueous HCl (0.08 mL, 0.61 mmol) was added. The reaction was heated at reflux for 6 h. More 4, 4-diethoxy-N-methylbutan-1-amine (90 mg, 0.51 mmol) was added at 60° C. and more 28% aqueous HCl (0.19 mL, 1.46 mmol) was added at 90° C. The reaction was heated to reflux for a further 8 h. The reaction was cooled and concentrated under reduced pressure. The red-brown residue was subjected to column chromatography (silica gel, eluent: EtOAc followed by EtOAc:EtOH:NH4OH 90:10:1) to give a brown oil (243 mg, 74%).
Reaction SMILES: [N+:1]([C:4]1[C:13]2[O:12][CH2:11][CH2:10][O:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.C1C2C(=C(N[C:24](=[O:26])[CH3:25])C=CC=2)CC1.C1(NC(=O)C)C2CCCCC=2C=CC=1>>[O:9]1[C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([NH:1][C:24](=[O:26])[CH3:25])[C:13]=2[O:12][CH2:11][CH2:10]1
Reactant: O=[N+]([O-])c1cccc2c1OCCO2
Reactant: CC(=O)Nc1cccc2c1CCC2
Agent: CC(=O)Nc1cccc2c1CCCC2
Product: CC(=O)Nc1cccc2c1OCCO2

Procedure:
Compound 8C was prepared from 8B by procedures analogous to those described in Experiment 3A and 2A.
Reaction SMILES: [C:1]([N:5]1[CH2:8][C:7]([N+:12]([O-:14])=[O:13])([N+:9]([O-:11])=[O:10])[CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:15]C(OCC1C=CC=CC=1)=O.CC(=C)C>C(Cl)(Cl)Cl>[ClH:15].[C:1]([N:5]1[CH2:6][C:7]([N+:12]([O-:14])=[O:13])([N+:9]([O-:11])=[O:10])[CH2:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)OCc1ccccc1
Agent: C=C(C)C
Agent: CC(C)(C)N1CC([N+](=O)[O-])([N+](=O)[O-])C1
Solvent: ClC(Cl)Cl
Product: Cl

Procedure:
To 1-tertiary-butyl-3,3-dinitroazetidine (20 g, 0.099 mole) in 25 milliliters (ml) of chloroform was added benzyl chloroformate (9.24 g, 0.054 mole). The mixture was stirred under reflux for 24 hours during which time isobutylene was generated and a white precipitate was formed. The mixture was allowed to cool and was the precipitate was separated by filtration. The filter cake was washed with methylene chloride, air dried and weighed to yield 6.4 g (27%) of 1-tertiary-butyl-3,3-dinitroazetidine hydrochloride. The filtrate was evaporated under vacuum to yield a yellow solid. This solid was taken up in warm toluene, the mixture filtered while hot, and the filtrate treated with hexanes to crystallize the product. The resultant product was collected by filtration and dried to give 7.3 g (26% yield) of pure 1-(benzyloxycarbonyl)-3,3-dinitroazetidine. The melting point of the product was 77.5°-78°. Later runs with longer reaction times between the 1-tertiary-butyl-3,3-dinitroazetidine and benzyl chloroformate in refluxing methylene chloride afforded higher yields.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:15](O)(=O)[CH3:16].[CH3:19]O>CC(C)=O>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH:15]([CH3:16])[CH3:19])[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)O
Reactant: CO
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CC(C)=O
Product: CC(C)N1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5.0 g Piperidin-4-yl-carbamic acid tert-butyl ester in 15 mL methanol, 7.34 mL acetone, 3.14 g Na(CN)BH3 and 0.3 mL acetic acid were added. After stirring for 16 h at RT the solvent was removed under reduced pressure and the residue was partitioned between 30 mL of water and 30 mL of ethyl acetate. The organic layer was washed with saturated Na2CO3 solution, water and then dried over Na2SO4. Following filtration, the solvent was removed under reduced pressure to yields a white solid. Yield: 4.8 g MS (ES+): m/e=243.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:6][CH2:5][C:4]([CH:10]([CH3:12])[CH3:11])([C:7]([OH:9])=O)[CH2:3]1.Cl.[F:14][C:15]([F:29])([F:28])[C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:19]N.C[N:31](C1C=CC=CN=1)C.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>ClCCl>[F:14][C:15]([F:28])([F:29])[C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:23]=1)[CH2:19][CH:3]1[C:2](=[CH2:1])[CH2:6][CH2:5][C:4]1([CH:10]([CH3:12])[CH3:11])[C:7]([NH2:31])=[O:9]
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CN(C)c1ccccn1
Reactant: C=C1CCC(C(=O)O)(C(C)C)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=C1CCC(C(N)=O)(C(C)C)C1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 31 %

Procedure:
The solution of 3-methylene-1-isopropylcyclopentanecarboxylic acid from the previous step (1.25 g, 7.44 mmol) 3,5-bis(trifluoromethyl)benzylamine hydrochloride (2.08 g, 7.44 mmol), dimethylaminopyridine (111.0 mg, 0.91 mmol) and diisopropylethylamine (1.29 mL, 7.44 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC, 2.85 g, 14.9 mmol) in dichloromethane (50 mL) was stirred at room temperature for 24 hrs. The reaction mixture was diluted with dichloromethane (100 mL) and washed with water (3×50 mL), brine (1×50 mL), dried (anhydrous sodium sulfate) and the solvent was evaporated under reduced pressure. The crude product was purified via mplc (Lobar Fertigsaule, LiChroprep, 40-63 μm, ethyl acetate/hexanes (1:4)) yielding 910 mg (31%) of pure product. 1H NMR (500 MHz, CDCl3): 7.76 (s, 1H1), 7.70 (s, 2H), 6.20 (bs, 1H), 4.95 (bs, 1H), 4.88 (bs, 1H), 4.65 (dd, J=15.70, 6.40 Hz, 1H), 4.50 (dd, J=15.50, 5.70 Hz, 1H), 2.68 (bd, J=16.20 Hz, 1H), 2.50 to 2.10 (bm, 4H), 1.96 (h, J=6.9 Hz, 1H), 1.74 (m, 1H), 0.87 (d, J=6.9 Hz, 3H), 0.85 (d, J=7.3 Hz, 31).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][C:13]4[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=4[C:11]=3[CH:10]=[C:9]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:4][C:3]=1[C:27](OC)=O.[OH-:31].[NH4+:32].CN(C)C=O>O>[C:27]([C:3]1[CH:4]=[C:5]([N:8]2[C:16]3[CH2:15][CH2:14][C:13]4[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=4[C:11]=3[CH:10]=[C:9]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:7][C:2]=1[OH:1])(=[O:31])[NH2:32]
Reactant: [OH-]
Reactant: COC(=O)c1cc(-n2c(-c3ccccc3)cc3c2CCc2ccccc2-3)ccc1O
Reactant: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-n2c(-c3ccccc3)cc3c2CCc2ccccc2-3)ccc1O

Procedure:
A mixture of 2.0 g. (0.005 mole) of 4,5-dihydro-3-(4-hydroxy-3-methoxycarbonylphenyl)2-phenylbenz[e]indole, 75 ml. of ammonium hydroxide, and 40 ml. of dimethyl formamide was heated under reflux for 3 hours, cooled, diluted with water, acidified, and extracted with ether. The ether phase was dried over sodium sulfate and concentrated to a solid. Recrystallization from benzene gave 1.21 g. (63%) of colorless crystals, m.p. 213°-215°.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH2:10][CH2:11][O:12][CH2:13][C:14](O)=[O:15])[CH:8]=[CH:9][C:2]1=2.B.[Na].C(OCC)(=O)C.Cl>O1CCCC1.O>[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][OH:15])[CH:8]=[CH:9][C:2]1=2
Reactant: O=C(O)COCCc1ccc2sccc2c1
Agent: B
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCCOCCc1ccc2sccc2c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 92.1 %

Procedure:
In 27 mL of tetrahydrofuran is dissolved 2.70 g of 2-(2-benzo[b]thiophen-5-ylethoxy)-acetic acid. At an ice-cooled temperature, 0.65 g of sodium boron hydride is added to the solution, and stirred at the same temperature as above for 10 minutes. Then, at an ice-cooled temperature, 3.24 g of boron trifluoride diethyl ether complex is added to the reaction mixture over a period of 20 minutes, and the resulting mixture is stirred at the same temperature as above for 30 minutes and then at ambient temperature for 2 hours. The reaction mixture is introduced into a mixture of ethyl acetate and water, pH is adjusted to 1.0 with 2 mol/L hydrochloric acid, and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is purified by column chromatography (eluent: n-hexane:ethyl acetate=3:1 to 2:1) to obtain 2.34 g of 2-(2-benzo[b]thiophen-5-ylethoxy)-1-ethanol as an oily product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)/[C:6]([CH3:18])=[C:5]2[CH2:19][CH2:20][O:21][NH2:22].[O:23]=[C:24]([CH3:28])[C:25](O)=[O:26]>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=1)/[C:6]([CH3:18])=[C:5]2[CH2:19][CH2:20][O:21][N:22]=[C:25]([OH:26])[C:24](=[O:23])[CH3:28]
Reactant: CC(=O)C(=O)O
Reactant: CC1=C(CCON)c2cc(F)ccc2/C1=C\c1ccncc1
Product: CC(=O)C(O)=NOCCC1=C(C)/C(=C/c2ccncc2)c2ccc(F)cc21

Procedure:
The title compound is prepared by reaction of O-2-[Z-5-fluoro-2-methyl-1-(4-pyridyl)methylene-1H-inden-3-yl]ethyl hydroxylamine with 2-oxopropionic acid by the method of Example 1.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][C:12]1[CH:13]2[CH2:18][CH:15]([CH2:16][CH:17]=1)[C:14]2([CH3:20])[CH3:19].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH2:11][C:12]2[CH:13]3[CH2:18][CH:15]([CH2:16][CH:17]=2)[C:14]3([CH3:19])[CH3:20])=[CH:4][CH:3]=1
Reactant: Oc1ccc(I)cc1
Reactant: CC1(C)C2CC=C(CCBr)C1C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)C2CC=C(CCOc3ccc(I)cc3)C1C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.2 %

Procedure:
A mixture of 4-iodophenol (0.4 g; 1.82 mmol), 2-(2-bromoethyl)-6,6-dimethylbicyclo[3.1.1]hept-2-ene (0.45 g, 1.97 mmol) and K2CO3 (0.3 g, 2.17 mmol) in anhydrous DMF (5 ml) was stirred overnight at room temperature. Another portion of 2-(2-bromoethyl)-6,6-dimethylbicyclo[3.1.1]hept-2-ene (0.3 g) was added and stirring was continued for 6 h. The mixture was diluted to 50 ml with EtOAc and washed with H2O (50 ml). The organic layer was separated, dried over MgSO4 and filtered. The filtrate was evaporated to dryness and the residue was purified by FCC (SiO2) to give the title product (0.189 g; 28%), as pale paste. 1H-NMR (CDCl3) 0.81 (s, 3H); 1.26 (s, 3H); 2.06-2.44 (m, 8H); 3.91 (tr, 2H, J=6.97 Hz); 5.32 (s, 1H); 6.64 (d, 2H, J=8.96 Hz); 7.51 (d, 2H, J=8.96 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:43])[CH2:5][CH2:6][C:7]([C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[N:18]([CH2:22][CH:23]([CH2:28][CH3:29])[CH2:24][CH2:25][CH2:26][CH3:27])[C:17]1[C:12]2=[CH:13][C:14]([C:34](=[O:42])[C:35]2[CH:40]=[CH:39][C:38](F)=[CH:37][CH:36]=2)=[C:15]2[CH:33]=[CH:32][CH:31]=[CH:30][C:16]2=1)=[O:8])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH:50]1[C:62]2[NH:61][C:60]3[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=3)[C:54]=2[CH:53]=[CH:52][CH:51]=1.O>CS(C)=O>[CH2:1]([O:3][C:4](=[O:43])[CH2:5][CH2:6][C:7]([C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[N:18]([CH2:22][CH:23]([CH2:28][CH3:29])[CH2:24][CH2:25][CH2:26][CH3:27])[C:17]1[C:12]2=[CH:13][C:14]([C:34](=[O:42])[C:35]2[CH:40]=[CH:39][C:38]([N:61]3[C:62]4[CH:50]=[CH:51][CH:52]=[CH:53][C:54]=4[C:55]4[C:60]3=[CH:59][CH:58]=[CH:57][CH:56]=4)=[CH:37][CH:36]=2)=[C:15]2[CH:33]=[CH:32][CH:31]=[CH:30][C:16]2=1)=[O:8])[CH3:2]
Reactant: CCCCC(CC)Cn1c2ccc(C(=O)CCC(=O)OCC)cc2c2cc(C(=O)c3ccc(F)cc3)c3ccccc3c21
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCC(CC)Cn1c2ccc(C(=O)CCC(=O)OCC)cc2c2cc(C(=O)c3ccc(-n4c5ccccc5c5ccccc54)cc3)c3ccccc3c21
Temperature: 150 °C
Reaction time: 8 h

Procedure:
To 4-(11-(2-ethylhexyl)-5-(4-fluoro-benzoyl)-11H-benzo[a]carbazol-8-yl]-4-oxo-butyric acid ethyl ester (1.01 g, 1.75 mmol) in dimethylsulfoxide (DMSO) (10 mL) are added K2CO3 (738 mg, 5.33 mmol) and carbazole (297 mg, 1.77 mmol). The reaction mixture is heated to 150° C. and stirred overnight. After cooling to room temperature, the reaction mixture is poured into water, and the crude product is extracted with CH2Cl2. The organic layer is washed with water and brine, dried over MgSO4. After concentration, the crude product is purified by column chromatography on silica gel eluting with CH2Cl2 to obtain a brown resin (760 mg; 60%). The structure is confirmed by 1H-NMR spectrum (CDCl3). δ [ppm]: 0.84 (t), 0.92 (t), 1.20-1.52 (m), 2.28-2.36 (m), 2.82 (t), 3.48 (t), 4.16 (q), 4.74-4.21 (m), 7.33 (t), 7.46 (t), 7.60 (d), 7.63 (d), 7.68 (t), 7.72 (t), 7.77 (d), 8.15 (t), 8.19 (d), 8.22 (d), 8.50 (s), 8.58 (d), 8.67 (d), 8.81 (s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:39][CH3:40])=[C:6]([C:8]([CH3:38])([CH3:37])[CH2:9][C:10]([OH:36])([C:32]([F:35])([F:34])[F:33])[CH2:11][NH:12][C:13]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]3[C:14]=2[CH:15]=[N:16][N:17]3[C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26](O)=[O:27])[CH:7]=1.[NH:41]1[CH2:48][CH2:47][CH2:46][C@@H:42]1[C:43]([NH2:45])=[O:44]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:39][CH3:40])=[C:6]([C:8]([CH3:37])([CH3:38])[CH2:9][C:10]([OH:36])([C:32]([F:34])([F:35])[F:33])[CH2:11][NH:12][C:13]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]3[C:14]=2[CH:15]=[N:16][N:17]3[C:23]2[CH:24]=[C:25]([C:26]([N:41]3[CH2:48][CH2:47][CH2:46][C@@H:42]3[C:43]([NH2:45])=[O:44])=[O:27])[CH:29]=[CH:30][CH:31]=2)[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1cccc(C(=O)O)c1)C(F)(F)F
Reactant: NC(=O)[C@H]1CCCN1
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1cccc(C(=O)N2CCC[C@@H]2C(N)=O)c1)C(F)(F)F

Procedure:
Prepared similarly to Example 1 from 3-(4-{[4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazol-1-yl)benzoic acid and D-prolinamide.
Reaction SMILES: Cl.[F:2][C:3]1[C:11]2[NH:10][C:9](=[O:12])[N:8]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:7]=2[CH:6]=[C:5]([CH3:19])[C:4]=1[F:20].[O:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1.CC(C)(O)[C:30]#[N:31].S([O-])([O-])(=O)=O.[Mg+2]>CC(N(C)C)=O>[F:2][C:3]1[C:11]2[NH:10][C:9](=[O:12])[N:8]([CH:13]3[CH2:14][CH2:15][N:16]([C:24]4([C:30]#[N:31])[CH2:25][CH2:26][O:21][CH2:22][CH2:23]4)[CH2:17][CH2:18]3)[C:7]=2[CH:6]=[C:5]([CH3:19])[C:4]=1[F:20]
Reactant: O=C1CCOCC1
Reactant: CC(C)(O)C#N
Reactant: Cc1cc2c([nH]c(=O)n2C2CCNCC2)c(F)c1F
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(=O)N(C)C
Product: Cc1cc2c([nH]c(=O)n2C2CCN(C3(C#N)CCOCC3)CC2)c(F)c1F
Temperature: 60 °C
Reaction time: 8 h

Procedure:
4,5-Difluoro-6-methyl-1-(4-piperidinyl)-1,3-dihydro-2H-benzimidazol-2-one hydrochloride (D23, 90 mg, 0.3 mmol) was converted to its free base using SCX, and this was then mixed with tetrahydro-4H-pyran-4-one (100 mg, 1.2 mmol), acetone cyanohydrin (100 mg, 1.2 mmol), magnesium sulfate (0.33 g) and dimethylacetamide (1 ml). The mixture was stirred under a slow stream of argon at 60° C. overnight, then partitioned between water and dichloromethane. Drying and evaporation gave the crystalline title compound from diethyl ether, 70 mg.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:6]([CH:22]=1)[CH2:7][NH:8][C:9]1[CH:21]=[CH:20][C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:11][CH:10]=1.[CH3:31][O:32][C:33](=[O:42])[C:34]1[CH:39]=[CH:38][C:37]([CH2:40]Br)=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[C:6]([CH:22]=1)[CH2:7][N:8]([C:9]1[CH:21]=[CH:20][C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:11][CH:10]=1)[CH2:40][C:37]1[CH:36]=[CH:35][C:34]([C:33]([O:32][CH3:31])=[O:42])=[CH:39][CH:38]=1
Reactant: CC(C)(C)OC(=O)c1ccc(NCc2cc(Br)ccc2OCc2ccccc2)cc1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN(Cc2cc(Br)ccc2OCc2ccccc2)c2ccc(C(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
tert-Butyl 4-[5-bromo-2-benzyloxybenzylamino]benzoate (16.9 g) and methyl-4-bromomethylbenzoate were dissolved in in dimethylformamide (30 ml) and potassium carbonate (18 g) added. The mixture was stirred at ambient temperature for 24 hours and then poured into water (300 ml). The reaction mixture was extracted with ether (4×100 ml). The combined ether extracts were washed with water (3×100 ml) and brine (1×100 ml), dried over magnesium sulphate and evaporated. The residue was purified by MPLC eluting with 1:1 dichloromethane/hexane to give tert-butyl 4-[N-(5-bromo-2-benzyloxybenzyl)-N-(4-methoxycarbonylbenzyl)amino]benzoate (3.6 g) m.p. 154-155° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@H:19]2[C@@H:10]([N:11]([CH2:26][C:27](O)=[O:28])[C:12](=[O:25])[C:13]3[C:14]([C:21]([F:24])([F:23])[F:22])=[CH:15][CH:16]=[CH:17][C:18]=32)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+]>C1COCC1.O>[OH:28][CH2:27][CH2:26][N:11]1[C@H:10]2[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:20][C@@H:19]2[C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([C:21]([F:23])([F:22])[F:24])[C:13]=2[C:12]1=[O:25]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2c3cccc(C(F)(F)F)c3C(=O)N(CC(=O)O)[C@H]2C1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H]2c3cccc(C(F)(F)F)c3C(=O)N(CCO)[C@H]2C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a solution of 2-((3aR,9bS)-2-(tert-butoxycarbonyl)-5-oxo-6-(trifluoromethyl)-1,2,3,3a-tetrahydro-5H-pyrrolo[3,4-c]isoquinolin-4(9bH)-yl)acetic acid from Example 19, Part A (70 mg, 0.17 mmol) in 4 mL of THF at 0° C. was added triethylamine (0.028 mL, 0.20 mmol) and ethyl chloroformate (0.019 mL, 0.20 mmol). The reaction was allowed to stir for 30 min at 0° C. and then there was added sodium borohydride (19 mg, 0.51 mmol) in a minimal amount of water. The resulting mixture was stirred for 1 h at 0° C. and then was quenched with 10 mL of 1N HCl. The mixture was extracted with ethyl acetate and the organics were washed with sat'd aq NaHCO3 and brine, dried (MgSO4), filtered through a pad of silica gel and concentrated in vacuo to afford 60 mg (88%) of the title compound which was sufficiently pure to be used without purification. LRMS (ESI): 401.21 (M+H)+.